Treating Sexual Desire Disorders with Flibanserin

ABSTRACT

The invention relates to the use of flibanserin, or a pharmaceutically acceptable acid addition salt thereof, for the treatment of disorders of sexual desire.

RELATED APPLICATIONS

Benefit of U.S. Provisional Application Ser. No. 60/348,911, filed onOct. 23, 2001 is hereby claimed, and said provisional application isherein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to the use of flibanserin for the preparation of amedicament for the treatment of disorders of sexual desire.

BACKGROUND OF THE INVENTION

The compound1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one(flibanserin) is disclosed in form of its hydrochloride in EuropeanPatent Application EP-A.-526434 and has the following chemicalstructure:

Flibanserin shows affinity for the 5-HT1A and 5-HT2-receptor. It istherefore a promising therapeutic agent for the treatment of a varietyof diseases, for instance depression, schizophrenia, and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

In studies of male and female patients suffering from sexual dysfunctionit has been found that flibanserin optionally in form of thepharmacologically acceptable acid addition salts thereof displays sexualdesire enhancing properties. Accordingly, the instant invention relatesto the use of flibanserin, optionally in form of the pharmacologicallyacceptable acid addition salts thereof for the preparation of amedicament for the treatment of disorders of sexual desire.

In a preferred embodiment the invention relates to the use offlibanserin, optionally in form of the pharmacologically acceptable acidaddition salts thereof for the preparation of a medicament for thetreatment of disorders selected from the group consisting of HypoactiveSexual Desire Disorder, loss of sexual desire, lack of sexual desire,decreased sexual desire, inhibited sexual desire, loss of libido, libidodisturbance, and frigidity.

Particular preferred according to the invention is the use offlibanserin, optionally in form of the pharmacologically acceptable acidaddition salts thereof for the preparation of a medicament for thetreatment of disorders selected from the group consisting of HypoactiveSexual Desire Disorder, loss of sexual desire, lack of sexual desire,decreased sexual desire, inhibited sexual desire.

In a particularily preferred embodiment the invention relates to the useof flibanserin, optionally in form of the pharmacologically acceptableacid addition salts thereof for the preparation of a medicament for thetreatment of disorders selected from the group of Hypoactive SexualDesire Disorder and loss of sexual desire.

The observed effects of flibanserin can be achieved in men and women.However, according to a further aspect of the invention the use offiibanserin optionally in form of the pharmacologically acceptable acidaddition salts thereof for the preparation of a medicament for thetreatment of female sexual dysfunction is preferred.

The beneficial effects of flibanserin can be observed regardless ofwhether the disturbance existed lifelong or was acquired, andindependent of etiologic origin (organic—both, physically and druginduced—, psychogen, a combination of organic—both, physically and druginduced—, and psychogen, or unknown).

Flibanserin can optionally used in form of its pharmaceuticallyacceptable acid addition salts. Suitable acid addition salts include forexample those of the acids selected from, succinic acid, hydrobromicacid, acetic acid, furnaric acid, maleic acid, methanesulphonic acid,lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid,tartaric acid and citric acid. Mixtures of the abovementioned acidaddition salts may also be used. From the aforementioned acid additionsalts the hydrochloride and the hydrobromide, particularily thehydrochloride, are preferred.

Flibanserin, optionally used in form of its pharmaceutically acceptableacid addition salts, may be incorporated into the conventionalpharmaceutical preparation in solid, liquid or spray form. Thecomposition may, for example, be presented in a form suitable for oral,rectal, parenteral administration or for nasal inhalation: preferredforms includes for example, capsules, tablets, coated tablets, ampoules,suppositories and nasal spray. The active ingredient may be incorporatedin excipients or carriers conventionally used in pharmaceutical.compositions such as, for example, talc, arabic gum, lactose, gelatine,magnesium stearate, corn starch, acqueous or non acqueous vehicles,polyvynil pyrrolidone, semisynthetic glicerides of fatty acids,benzalconium chloride, sodium phosphate, EDTA, polysorbate 80. Thecompositions are advantageously formulated in dosage units, each dosageunit being adapted to supply a single dose of the active ingredient. Thedosis range applicable per day is between 0.1 to 400, preferably between1.0 to 300, more preferably between 2 to 200 mg.

-   Each dosage unit may conveniently contain from 0.01 rug to 100 mg,    preferably from 0.1 to 50 mg,

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g. of a flavouring such as vanilline or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g of with theaddition of preservatives such as p-hydroxybenzoates, or stabiliserssuch as alkali metal salts of ethylenediamine tetraacetic acid, andtransferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made. for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

The Examples which follow illustrate the present invention withoutrestricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet flibanserin hydrochloride 100 mg lactose 240 mgcorn starch 340 mg polyvinylpyrrolidone  45 mg magnesium stearate  15 mg740 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, is kneaded, wet-granulatedand dried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet flibanserin hydrochloride 80 mg corn starch 190mg  lactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone15 mg sodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodium-carboxy-methyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Coated tablets per coated tablet flibanserin hydrochloride  5 mg cornstarch 41.5 mg   lactose 30 mg polyvinylpyrrolidone  3 mg magnesiumstearate 0.5 mg  80 mg

The active substance, corn starch, lactose and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax.

D) Capsules per capsule flibanserin hydrochloride 150 mg Corn starch268.5 mg Magnesium stearate 1.5 mg 420 mg

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry grannies are screened andmixed with magnesium stearate. The finished mixture is packed into sizeI hard gelatine capsules.

E) Ampoule solution flibanserin hydrochloride 50 mg sodium chloride 50mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion.

F) Suppositories flibanserin hydrochloride  50 mg solid fat 1650 mg 1700mg

The hard fat is melted, At 40° C. the ground active substance ishomogeneously dispersed. It is cooled to 38° C. and. poured intoslightly chilled suppository moulds.

1. A method of treating decreased sexual desire in a patient, comprisingadministering a therapeutically effective amount of flibanserin or apharmaceutically acceptable acid addition salt thereof to the patient totreat decreased sexual desire.
 2. The method according to claim 1wherein the patient is female.
 3. The method according to claim 1,wherein the patient is male.
 4. The method according to claim 1, whereinthe amount administered is between about 0.1 mg and 400 mg per day offlibanserin or a pharmaceutically acceptable acid addition salt thereof.5. The method according to claim 1, wherein the amount administered isbetween about 1 mg and 300 mg per day of flibanserin or apharmaceutically acceptable acid addition salt thereof.
 6. The methodaccording to claim 1, wherein the amount administered is in a dosageunit containing between about 0.01 mg and 100 mg of flibanserin or apharmaceutically acceptable acid addition salt thereof.
 7. The methodaccording to claim 1, wherein the amount administered is in a dosageunit containing between about 0.1 mg and 50 mg of flibanserin or apharmaceutically acceptable acid addition salt thereof.
 8. A method oftreating absent sexual desire in a patient, comprising administering atherapeutically effective amount of flibanserin or a pharmaceuticallyacceptable acid addition salt thereof to the patient to treat decreasedsexual desire.
 9. The method according to claim 8, wherein the patientis female.
 10. The method according to claim 8, wherein the patientmale.
 11. The method according to claim 8, wherein the amountadministered is between about 2 mg and 200 mg per day of flibanserin ora pharmaceutically acceptable acid addition salt thereof.
 12. The methodaccording to claim 8, wherein the amount administered is between about0.1 mg and 100 mg per day of flibanserin or a pharmaceuticallyacceptable acid addition salt thereof.
 13. The method according to claim8, wherein the amount administered is in a dosage unit containing about150 mg of flibanserin or a pharmaceutically acceptable acid additionsalt thereof.
 14. A method of treating inhibited sexual desire in apatient, comprising administering a therapeutically effective amount offlibanserin or a pharmaceutically acceptable acid addition salt thereofto the patient to treat decreased sexual desire.
 15. The methodaccording to claim 14, wherein the patient
 16. The method according toclaim 14, wherein the patient is male.
 17. The method according to claim14, wherein the amount administered is between about 0.1 mg and 400 mgper day of flibanserin or a pharmaceutically acceptable acid additionsalt thereof.
 18. The method according to claim 14, wherein the amountadministered is in a dosage unit containing about 100 mg of flibanserinor a pharmaceutically acceptable acid addition salt thereof.
 19. Themethod according to claim 14, wherein the amount administered is in adosage unit containing about 80 mg of flibanserin or a pharmaceuticallyacceptable acid addition salt thereof.
 20. The method according to claim14, wherein the amount administered is in a dosage unit containing about50 mg of flibanserin or a pharmaceutically acceptable acid addition saltthereof.